Mnogie nowotwory pierwotne u kobiet nosicielek mutacji genu BRCA1 – dwa przypadki kliniczne

Mutations of BRCA1 and BRCA2 genes account for the majority of hereditary breast and ovarian cancers. So far, risk-reducing salpingo-oophorectomy has been the most effective strategy for gynecological cancer prevention in susceptibility gene mutation carriers. It does not prevent, however, from the occurrence of primary peritoneal cancer. We present two clinical cases of patients with the BRCA1 gene mutation. Both patients had a family history of cancer and both were presenting with metachronic malignances. The first patient, whose mother suffered from breast and ovarian cancer, was diagnosed with left breast cancer in 2004. The patient was 44 years old at diagnosis. Genetic testing revealed the BRCA1 gene mutation. A breast conserving therapy (BCT) was conducted, followed by chemotherapy, radiotherapy and immunotherapy with trastuzumab due to HER2 overexpression. Due to BRCA1 mutation, in November 2005, prophylactic hysterectomy with appendages was performed. Histological examination revealed bilateral ovarian cancer (adenocarcinoma G3) with metastasis to the paraaortal lymph node. The patient received six cycles of chemotherapy: paclitaxel and carboplatin. Ovarian cancer relapsed 3 years later. After that the patient received 5 lines of chemotherapy and finally died due to disease progression in September 2011. The second patient, a 49-year-old woman, was diagnosed with breast cancer in July 2003 and subsequently treated with neoadjuvant chemotherapy, breast conserving surgery and radiotherapy. Genetic testing was also performed and revealed the BRCA1 gene mutation. A year earlier the patient had undergone hysterectomy with appendages due to uterine myomas. Three of her five sisters suffered from breast and ovarian cancer. The patient’s father died of colorectal cancer. The patient remained under surveillance. Because of the increasing level of Ca-125 (since October 2004), PET-CT was performed and revealed a tumor lesion of the peritoneum. Histological examination from the biopsy confirmed primary peritoneal cancer (papillary serous adenocarcinoma – primary peritoneal carcinoma). Reexamination of the tissues from hysterectomy with appendages was also performed and revealed an adenocarcinoma in the right ovary. Pathologic examination excluded metastasis of a breast cancer. Pathomorphology of the ovarian lesion was also different than in the lesions of the peritoneum. Thus, three different tumor types (breast, ovarian and peritoneal cancer) coexisted independently. The patient received chemotherapy: paclitaxel and cisplatin. Later on, due to disease progression she was treated with five consecutive chemotherapy regimens and hormonal therapy. The patient died in January 2008. These case illustrate that genetic diagnosis may be critical for the overall treatment plan.Za większość przypadków dziedzicznego raka piersi i jajnika odpowiadają mutacje genów BRCA. Obecnie najskuteczniejszą metodą prewencji raka jajnika jest obustronne usunięcie przydatków, niegwarantujące jednak zahamowania rozwoju pierwotnego raka otrzewnej. Przedstawiono przypadki dwóch chorych, z dodatnim wywiadem rodzinnym, mutacją genu BRCA1, u których stwierdzono nowotwory metachroniczne. U pierwszej chorej, której matka chorowała na nowotwór piersi i jajnika, w 2004 r. rozpoznano raka piersi lewej. Zastosowano operację oszczędzającą, uzupełniającą chemioterapię, radioterapię oraz immunoterapię trastuzumabem z uwagi na nadekspresję HER2. Ze względu na mutację genu BRCA1 u chorej wykonano operację profilaktycznego usunięcia macicy z przydatkami. Badanie histopatologiczne wykazało ognisko gruczolakoraka w obu jajnikach oraz w węźle chłonnym paraaortalnym. Zastosowano VI cykli chemioterapii: paklitaksel i karboplatyna. Nawrót raka jajnika stwierdzono trzy lata później. Chora otrzymała kolejnych V linii chemioterapii i zmarła w sierpniu 2011 r. z powodu progresji choroby. Druga chora, 49-letnia, leczona od lipca 2003 r. z powodu raka piersi prawej – neoadjuwantowa chemioterapia, BCT, radioterapia. U chorej stwierdzono mutację genu BRCA1. Rok wcześniej usunięto macicę z przydatkami z powodu mięśniaków. Trzy z pięciu sióstr kobiety chorowały na raka piersi i jajnika. Ojciec chorej zmarł z powodu raka jelita grubego. Chora pozostawała pod ścisłą kontrolą. Z powodu narastającego stężenia markera Ca-125 (od października 2004 r.) wykonano PET-TK, stwierdzając nowotworowe zajęcie otrzewnej. Badanie histopatologiczne materiału biopsyjnego wykazało gruczolakoraka otrzewnej, a ponowna ocena materiału z operacji usunięcia macicy z przydatkami, ognisko gruczolakoraka w jajniku prawym. Histopatolog wykluczył przerzut raka piersi i jednoznacznie określił odmienność morfologii zmian w otrzewnej od zmiany w jajniku. U chorej rozpoznano trzy niezależne nowotwory. Zastosowano chemioterapię: cisplatyna i paklitaksel. Następnie, z powodu progresji choroby, zastosowano V kolejnych linii chemioterapii oraz hormonoterapię. Chora zmarła w styczniu 2008 r

Combined Tumor Cell-Based Vaccination and Interleukin-12 Gene Therapy Polarizes the Tumor Microenvironment in Mice

Tumor progression depends on tumor milieu, which influences neovasculature formation and immunosuppression. Combining immunotherapy with antiangiogenic/antivascular therapy might be an effective therapeutic approach. The aim of our study was to elaborate an anticancer therapeutic strategy based on the induction of immune response which leads to polarization of tumor milieu. To achieve this, we developed a tumor cell-based vaccine. CAMEL peptide was used as a B16-F10 cell death-inducing agent. The lysates were used as a vaccine to immunize mice bearing B16-F10 melanoma tumors. To further improve the therapeutic effect of the vaccine, we combined it with interleukin (IL)-12 gene therapy. IL-12, a cytokine with antiangiogenic properties, activates nonspecific and specific immune responses. We observed that combined therapy is significantly more effective (as compared with monotherapies) in inhibiting tumor growth. Furthermore, the tested combination polarizes the tumor microenvironment, which results in a switch from a proangiogenic/immunosuppressive to an antiangiogenic/immunostimulatory one. The switch manifests itself as a decreased number of tumor blood vessels, increased levels of tumor-infiltrating CD4+, CD8+ and NK cells, as well as lower level of suppressor lymphocytes (Treg). Our results suggest that polarizing tumor milieu by such combined therapy does inhibit tumor growth and seems to be a promising therapeutic strategy

Direct in vivo transfer of plasmid DNA into murine tumors: Effects of endotoxin presence and transgene localization.

The purpose of this study was to investigate the effect of endotoxin presence in plasmid DNA preparations on the efficiency of transfection achieved in vivo with B16(F10) and Renca tumors and to determine transgene localization. Our data show that endotoxin markedly decreases the efficiency of transfection. Furthermore, the transgene transferred in vivo can be found in both neoplastic and normal (most likely myofibroblast) cells lying in proximity of the administration site

Direct transfer of IL-12 gene into growing Renca tumors.

We investigated the feasibility of transferring naked plasmid DNA containing a therapeutic gene (IL-12) into mice harboring growing Renca tumors. We found that naked DNA transferred into growing Renca and B16(F10) tumors gives higher expression level of reporter gene than complexes of DNA with DDAB/ DOPE or DC-Chol/DOPE. Transfer of naked DNA carrying the IL-12 gene into growing Renca tumors causes a distinct therapeutic effect that depends on the time span between inoculation of mice with cancer cells and the beginning of the therapy. Therapy started on day 3 resulted in total cure (100%) of mice

Treatment related toxicity in BRCA1-associated epithelial ovarian cancer – is DNA repairing impairment associated with more adverse events?

Aim of the study: The presence of BRCA germline mutations in patients with ovarian cancer has been shown to have predictive and prognostic significance, including increased platinum-sensitivity. The aim of the study was to evaluate if patients with BRCA1-associated ovarian cancer have more treatment related adverse events and, if so, does it have impact on chemotherapy outcomes. Material and methods : We conducted a retrospective analysis of medical records of 172 patients with newly diagnosed epithelial ovarian cancer, treated in Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch between 2007 and 2013. Ninety-six of these patients have known BRCA mutation status – 21 patients were BRCA1(+) and 75 BRCA1(–). Analysed treatment related adverse events (AE’s) were: haematological toxicity, nausea/vomiting, neuropathy and mucositis. Results : Grade 3–4 haematological AE’s were significantly more common among BRCA1(+) patients (OR = 3.86; 95% CI: 1.14–13.23; p = 0.02). There was no association between BRCA1 mutation status and neuropathy (p = 0.73) or nausea/vomiting (p = 0.91). Occurrence of above mentioned AE’s has no significant association with PFS (p = 0.75, 0.64, 0.97 respectively) and OS (p = 0.64, 0.69, 0.73 respectively). Conclusions : Among patients with BRCA1-associated epithelial ovarian cancer we observed significantly more grade 3–4 haematological complications after chemotherapy. However, occurrence of AE’s did not correlate with better outcomes in this subgroup